Significance of Signal Transduction Mechanisms in the Effects of Drugs. Tachyphylaxis and Tolerance to Drugs Flashcards
Signal Transduction
Pharmacological Significance
Allow variation of effects of certain drugs
Multiplies and amplifies effect
Triggers a cascade
Personalised Medicine; Disease Drug Interaction
Specific drug for specific patient for his disease
Which drugs most appropriate or CI
Main Types of Receptors
Ligand Gated Ion Channel
G Protein Coupled Receptor
Kinase Linked Receptors
Nuclear Receptors
Receptors
Specific glycoprotein
No other known function other than letting cell know about ligand binding
No function without agonist binding
Basic Mechanism of Drug Action on Receptors Ion Channels Enzymes Transporters
Receptors
Agonist, Antagonist
Ion Channel
Blockers, Modulators
Enzymes
Inhibitor, False substrate, Pro-drug
Transporters
Normal, Inhibitor, False Substrate
Ionotropic Receptors (Ligand Gated Ion Channels)
Structure
Examples
4-5 subunits
1 subunit consists of 4 transmembrane alpha helices
Ligand binding subunit in EC space
Very fast: milliseconds
Examples
ACh N R
GABA A R
5HT3 R
Direct channel opening-> hyperpolarisation or depolarisation-> cellular effects
G Protein Coupled Receptors
Metabotropic
1 polypeptide chain; 7 transmembrane alpha helices
EC ligand binding subunit
IC effector subunit
Signal transduction takes seconds to minutes
Examples
Muscarinic ACh R
M1: Gq (neuronal)
M2: Gi
M3: Gq (glandular)
G Protein Coupled Receptor
Effector: Adenylate Cyclase
Mediated Effects SM Relaxation Cardiac muscle contraction Increased neuronal excitability Increase of gastric acid secretion
Gs: Adrenergic Beta Receptors (1 and 2)
Dopamine D1 Receptor (dilation of renal vessels)
Histamine H2 Receptor (secretion of gastric acid)
Gi: ACh M2
Adrenergic alpha 2 Receptor (decrease further NA
release)
Dopamine D2 Receptor
G Protein Coupled Receptor
Effector: Phospholipase C
Mediated Effects SM Contraction Cardiac Muscle Contraction NT Release Hormone Secretion
Gq: ACh M1 and M3
Adrenergic alpha 1 Receptors-> vasoconstriction
Histamine H1 Receptor-> allergic reactions
Vasopressin, Angiotensin II
G Protein Coupled Receptor
Gq Signal Transduction Pathways
Activation of Phospholipase C-> IP3 and DAG release
from PIP2
IP3-> Ca from SR (this with DAG activates PK-C)
DAG-> activation PK-C-> phosphorylation of tissue
specific substrate enzymes
In SM: release of Ca from SR-> Ca-CM-> MLCK->
contraction
G Protein Coupled Receptor
Gs Signal Transduction Pathway
Adenylate cyclase: ATP-> cAMP
cAMP-> PK-A activation
PK-A phosphorylates a set of tissue specific substrate enzymes
Ex: Lipase, Glucose 1 Phosphatase
PK-A also phosphorylates transcription factors (ex CREB)
SM
Increase cAMP-> inhibition of MLCK-> relaxation
Cardiac Muscle
Increase cAMP-> Increase PK-A-> activation of Ca channel-> further release Ca from SR-> Contraction
G Protein Coupled Receptor
Effector: Phospholipase A2
From phospholipids of all cell membrane arachidonic acid
From that various eicosanoids are formed
Eicosanoids may act as 1st messengers (local hormones; autacoids)
or as second messengers inside cytoplasm
Endothelium Dep. Vasodilation
Endothelial Cell:
Ca activates NOS
NOS: L Arginine-> NO
NO then passes to SM
Activates G Cyclase: GTP-> cGMP-> G Kinase-> Relaxation
G Protein Coupled Receptor
Effector Ion Channels
Capable of directly influencing functions of K, Ca, and Na channels without usage of 2nd messengers
Example
M2 Muscarinic Agonist: Increases K permeability
Enzyme (Kinase) Linked Receptor
EC ligand binding and IC catalytic subunit
Signal transduction takes minutes to hours
Tyrosine Kinase Linked (Imatinib)
Guanylate Cyclase Linked (ANP) (increase cGMP)
Tyrosine Phosphatase Linked
Serine/Threonine Kinase Linked
Examples
GF
Insulin
Cytokines
GF Type
Autophosphoylation-> dimerisation-> Ras/Raf/Map (–> large signal amplification)
Cytokine R Type
JAK/STAT–> nucleus
Intracellular Receptors
Ligand binding subunit (C Terminal)
DNA binding subunit (central part)
Transcription activating subunit (N terminal)
Signal Transduction takes hours-> days
Agonist binding-> change of conformation-> dimerisation-> nucleus-> binding to HRE-> increased gene activation or gene repression transcription
Examples Steroid Hormones Thyroid Hormones Vit D Retinoids
Tachyphylaxis and Tolerance
Tachyphylaxis
Decreased drug action post continuous drug admin
within minutes or hours
Tolerance
Decreased drug action which develops slowly and
gradually within days/weeks
–> same dose evokes smaller effect; higher dose req. for same effect
Refractory: complete loss of absence of th effect. May be due to genetic variations: ex aspirin
Extent can differ for different drug actions
Opioids: marked tolerance for analgesic, not for ex
constipation, myosis
Can be basis for th application of drug
Ex: GnRH analogues
Mechanism can either be pharmacokinetic- or dynamic
Tachyphylaxis and Tolerance
Mechanisms
Changes in ligand binding or R activation (R desensiti.)
fast and marked
P of IC sites of R protein-> decreased potential to
induce signal transduction process
Decreased/ Increased # of Receptors (down/up regula.)
Slower process
Ex: Hormone R decrease when agonist admin
b2 R decrease when agonist conc is low
Depletion of Mediators: usually -> Tachyphylaxis
Ex: amphetamine depletes monoamine stores
nitrates deplete SH groups
Increased Degradation : Enzyme induction
Physiological Adaption–> Tolerance
Homeostatic counter reg act against drugs
Thiazine diuretics-> compensat. RAAS activation
Active Pumping Out
MDR
AB production against drug if drug behaves as ag
Ex: Insulin
